N-substituted derivatives of 4 (N-piperazinylmethyl) spiro dibenzocycloheptadi- (or tri-) ene-5, 2-dioxolane (1,3) their method of preparation and their application in therapeutics

ABSTRACT

Compounds of the formula ##STR1## wherein Z is --CH 2  CH 2  -- or --CH═CH--, and R is methyl, ethoxycarbonylmethyl or ##STR2## wherein ##STR3## is methylamino, n-propylamino, isopropylamino, dimethylamino, di(n-propyl)amino, morpholino, pyrrolidino or hexamethyleneimino. The compounds are prepared by reacting piperazine substituted with R, with 4&#39;-bromomethyl-5,2&#39;-spiro-dibenzocycloheptadi(or tri)ene-(1&#39;,3&#39;) dioxolan. The compounds possess cough-suppressing, spasmolytic, analgesic, respiratory analeptic, hypotensive, vasodilatory, antiarythmic, antiulcerous, antihistamine, sedative, anti-inflammatory, diuretic and antiserotonine properties.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a division of application Ser. No. 541,609, filed Jan. 16, 1975, which in turn is a continuation-in-part of application Ser. No. 263,409, filed June 16, 1972, now abandoned.

The present invention relates to new N'-substituted derivatives of 4'-(N-piperazinylmethyl)spiro dibenzocycloheptadi- (or tri-) ene-5,2'- dioxolane (1',3').

The compounds have the formula: ##STR4## in which: Z represents a --CH₂ --CH₃ -- group or a --CH═CH-- group, and

R represents:

Methyl, or

Ethoxycarbonylmethyl, or

Methylaminocarbonylmethyl, propylaminocarbonylmethyl, isopropylaminocarbonylmethyl, dimethylaminocarbonylmethyl, dipropylaminocarbonylmethyl, morpholinocarbonylmethyl, pyrrolidinocarbonylmethyl or hexamethyleneiminocarbonylmethyl, that is, compounds in which R is ##STR5## wherein ##STR6## is methylamino, n-propylamino, isopropylamino, dimethylamino, di(n-propyl)amino, morpholino, pyrrolidino or hexamethyleneimino.

The compounds are prepared reacting the bromomethyl-4'-spiro dibenzocycloheptadi- (or tri-)ene-5,2'-dioxolane (1',3') having as formula ##STR7## on a monosubstituted piperazine having as formula: ##STR8## in which R and Z have the same meaning as in formula (I).

The compound of formula (II) in itself obtained by reacting, in the presence of tin tetrchloride, epibromhydrin having the formula ##STR9## on dibenzo (a-d) cycloheptadi- (or tri-)enone having the formula:

The following preparation is given as a non-limiting example to illustrate the process.

EXAMPLE 4'-N'-(2",3"-dihydroxy "-propyl)N-piperazinyl methyl spiro dibenzo (a,d) cycloheptadiene-5:2' dioxolane (1',3') dimaleate.

Code number: 70405

In 300 ml of CHCl₃ are dissolved 62 g of dibenzocycloheptadienone and 11 g of SnCl₄. This mixture is cooled to 5° C., then 50 g of epibromhydrin in solution in 100 ml of CHCl₃ are slowly introduced; after 3 hours of contact at the same temperature caustic soda lye is added to alkalize the mixture, then the organic phase is washed several times with water. After concentration, a crude product is obtained which is recrystallized in isopropyl alcohol. After recrystallization 92 g of 4'-bromomethyl spiro dibenzo (a,d) cycloheptadiene-5:2' -dioxolane (1',3') are obtained.

In 300 ml of toluene are dissolved 34.5 g of the bromomethylated derivative thus prepared, then 16 g of sodium carbonate and 32 g of N-2,3 dihydroxy 1piperazine are introduced. It is refluxed while stirring for 8 hours, then, after cooling, 500 ml of water and 300 ml of ethyl acetate are added. After decantation, the organic solution is concentrated. The oily crude product obtained is treated in acetone with 23 g of maleic acid. The dimaleace obtained is separated by filtration and recrystallized in ethanol.

Melting point: 179° C.

Yield: 45%

The titre of the compound obtained, as potentiographically determined, is 99%. The water content, as determined by K. Fischer's method is 0.55%. The compounds listed in the following Table I were prepared by the same method of operation.

EXAMPLE 2 -4'-[N'-(di-n-propylaminocarbonylmethyl) N-piperazinyl methyl] spiro [dibenzo(a,d)cycloheptatriene-5:2' dioxolane (1',3')] dimaleate

To a solution of 0.4 mole of N-[di-n-propylaminocarbonylmethyl] piperazine in 500 ml of toluene, under reflux, there is added 0.2 mole of sodium carbonate and then 0.2 mole of bromomethyl-4'-spiro[dibenzocycloheptatriene-5:2' dioxolane (1',3']. Reflux is maintained for 8 hours. After cooling, 500 ml of water and 300 ml of ethyl acetate are added. After decantation, the organic solution is concentrated. The crude product is recrystallized from isopropyl ether. To a solution of 0.12 mole of the thus-obtained compound, in 700 ml of acetone, is added 0.24 mole of maleic acid in 150 ml of acetone. The crude dimaleate thus obtained is separated by filtration and is recrystallized from 400 ml of ethanol.

                                      TABLE I                                      __________________________________________________________________________      ##STR11##                                                                                                                Elementary analysis                 Code                 Empirical                                                                              Molecular                                                                            Melting Calculated                                                                               Found                     number                                                                              R               formula weight                                                                               point                                                                               yield                                                                             C   H  N  C   H  N                  __________________________________________________________________________     70358                                                                               CH.sub.3        C.sub.31 H.sub.36 N.sub.2 O.sub.10                                                     596,61                                                                               202° C                                                                       50%                                                                               62.40                                                                              6.08                                                                              4.70                                                                              62.41                                                                              6.03                                                                              4.87               70365                                                                               CH.sub.2 COOC.sub.2 H.sub.5                                                                    C.sub.34 H.sub.40 N.sub.2 O.sub.12                                                     668.67                                                                               156° C                                                                       69%                                                                               61.07                                                                              6.03                                                                              4.19                                                                              60.96                                                                              5.99                                                                              4.30               70347                                                                                ##STR12##      C.sub.35 H.sub.43 N.sub.3 O.sub.11                                                     681.71                                                                               188° C                                                                       39%                                                                               61.66                                                                              6.36                                                                              6.16                                                                              61.58                                                                              6.31                                                                              6.30               70357                                                                                ##STR13##      C.sub.36 H.sub.43 N.sub.3 O.sub.12                                                     709.72                                                                               198° C                                                                       48%                                                                               60.92                                                                              6.11                                                                              5.92                                                                              60.84                                                                              6.00                                                                              6.10               70339                                                                                ##STR14##      C.sub.36 H.sub.43 N.sub.3 O.sub.11                                                     693.72                                                                               174° C                                                                       68%                                                                               62.32                                                                              6.25                                                                              6.06                                                                              62.41                                                                              6.23                                                                              6.26               70374                                                                                ##STR15##      C.sub.39 H.sub.40 N.sub.2 O.sub.6                                                      632.72                                                                               209° C                                                                       31%                                                                               74.03                                                                              6.37                                                                              4.43                                                                              74.15                                                                              6.25                                                                              4.63                ##STR16##                                                                                                                Elementary Analysis                 Code                 Empirical                                                                              Molecular                                                                            Melting Calculated                                                                               Found                     number                                                                              R               formula weight                                                                               point                                                                               yield                                                                             C   H  N  C   H  N                  __________________________________________________________________________     72143                                                                               CH.sub.3        C.sub.31 H.sub.34 N.sub.2 O.sub.10                                                     594.59                                                                               176° C                                                                       58%                                                                               62.62                                                                              5.76                                                                              4.71                                                                              62.50                                                                              5.98                                                                              4.91               72196                                                                               CH.sub.2CHOHCH.sub.2 OH                                                                        C.sub.33 H.sub.38 N.sub.2 O.sub.12                                                     654.65                                                                               167° C                                                                       44%                                                                               60.54                                                                              5.85                                                                              4.28                                                                              60.34                                                                              5.95                                                                              4.48               72188                                                                               CH.sub.2CONHCH.sub.3                                                                           C.sub.33 H.sub.37 N.sub.3 O.sub.11,                                                    660.65                                                                               106° C                                                                       23%                                                                               59.99                                                                              5.80                                                                              6.36                                                                              59.81                                                                              5.71                                                                              6.52                                     H.sub.2 O                                                72134                                                                                ##STR17##      C.sub.35 H.sub.41 N.sub.3 O.sub.11                                                     679.70                                                                               170° C                                                                       79%                                                                               61.84                                                                              6.08                                                                              6.18                                                                              61.93                                                                              6.23                                                                              6.37               7251                                                                                 ##STR18##      C.sub.34 H.sub.39 N.sub.3 O.sub.11                                                     665.67                                                                               174° C                                                                       70%                                                                               61.34                                                                              5.91                                                                              6.31                                                                              61.14                                                                              5.88                                                                              6.42               7204                                                                                 ##STR19##      C.sub.30 H.sub.39 N.sub.3 O.sub.3 * C.sub.38                                   H.sub.47 N.sub.3 O.sub.11                                                              489.83 721.78                                                                        107° C 148° C                                                         78% 81%                                                                           73.59 63.23                                                                        8.03 6.56                                                                         8.58 5.82                                                                         73.52 65.06                                                                        8.12 6.48                                                                         8.72 5.80          71562                                                                                ##STR20##      C.sub.36 H.sub.41 N.sub.3 O.sub.11                                                     691.71                                                                               160° C                                                                       70%                                                                               62.51                                                                              5.97                                                                              6.08                                                                              62.51                                                                              6.01                                                                              5.93               71564                                                                                ##STR21##      C.sub.28 H.sub.33 N.sub.3 O.sub.4 * C.sub.36                                   H.sub.41 N.sub.3 O.sub.12                                                              475.56 707.71                                                                        155° C 153° C                                                         83% 66%                                                                            70.71 61.09                                                                       6.99 5.84                                                                         8.84 5.94                                                                         70.83 60.89                                                                        7.03 5.88                                                                         8.75 5.85          72176                                                                                ##STR22##      C.sub.38 H.sub.45 N.sub.3 O.sub.11                                                     719.76                                                                               154° C                                                                       49%                                                                               63.41                                                                              6.22                                                                              5.84                                                                              63.33                                                                              6.34                                                                              5.94               72142                                                                               CH.sub.2CONHC.sub.3 H.sub.7 (η)                                                            C.sub.35 H.sub.41 N.sub.3 O.sub.11                                                     679.70                                                                               165° C                                                                       41%                                                                               61.84                                                                              6.08                                                                              6.18                                                                              61.81                                                                              6.21                                                                              6.30               __________________________________________________________________________      *base                                                                    

The compounds of formula I were studied with laboratory animals and showed antiserotonine, anti-cough, spasmolytic, analgesic and respiratory analeptic, hypotensive, vasodilatory, antiarythmic, antiulcerous, antihistamine, sedative, antiinflammatory and diuretic properties. The compounds of formula I do not exhibit anti-depressive properties.

1. Anti-cough properties

The compounds of formula (I) administered intravenously and intraduodenally reduced the cough caused by stimulation of the upper laryngeal nerve in an anaesthetized cat. The results obtained with a certain number of these compounds are given in the following Table II:

                  Table II                                                         ______________________________________                                         Code number of                                                                             Dose         Reduction of cough                                    compound tested                                                                            administered intensity duration                                    ______________________________________                                         70357        2 mg/kg/IV  100%      20 mm                                       70358        25 mg/kg/ID 100%      >60 mm                                      70356        2 mg/kg/IV  100%      90 mm                                       70339        1 mg/kg/IV  100%      20 mm                                       70347        1 mg/kg/IV   80%      20 mm                                       70405       100 mg/kg/ID 100%      60 mm                                       ______________________________________                                    

2. Spasmolytic properties

Compounds of formula I, introduced in the survival medium, are capable of opposing the contacting action of barium chloride on the isolated duodenum of a rat. This activity is determined either by taking papaverine as the standard or by calculating the DE₅₀ of the compound tested. The results obtained with certain of these compounds are given in the following Tables III and IV.

                  Table III                                                        ______________________________________                                         Code number of                                                                 compound tested  Spasmolytic activity                                          ______________________________________                                         70357            1.5 × papaverine                                        70358            1.5 × papaverine                                        70365            3   × papaverine                                        70339            1   × papaverine                                        70347            1.5 × papaverine                                        ______________________________________                                    

                  Table IV                                                         ______________________________________                                         Code number of       DE.sub.50                                                 compound tested      μg/ml                                                  ______________________________________                                         72143                3.75                                                      72196                0.25                                                      7251                 3.50                                                      7204                 2.50                                                      71564                2.50                                                      72176                3.50                                                      72142                2.50                                                      ______________________________________                                    

3. Analgesic properties

The compounds of formula (I) administered orally to a mouse are capable of reducing the number of painful stretchings following the intraperitoneal injection of acetic acid.

By administering 100 mg/kg/PO of different compounds of formula (I) the results shown in the following Table V are obtained.

                  Table V                                                          ______________________________________                                                        Percentage reduction in                                         Code number of the number of painful                                           compound tested                                                                               stretchings (%)                                                 ______________________________________                                         70358          43                                                              70365          75                                                              70347          70                                                              70339          75                                                              72196          45                                                              72188          60                                                               7251          50                                                               7204          70                                                              71562          47                                                              72142          70                                                              ______________________________________                                    

4. Respiratory analeptic properties

The compounds of formula (I) administered intravenously to an anaesthetized guinea pig are capable of opposing respiratory depression caused by morphine. As an example, with a dose of 5 mg/kg/IV, compound 70358 increased respiratory frequency by 65%.

5. Hypotensive properties

Administered intravenously to an anaesthetized rat, the compounds of formula (I) cause a lowering of arterial pressure. The results obtained with a certain number of these compounds are shown in the following Table VI.

                  Table VI                                                         ______________________________________                                                                  Reduction of arter-                                   Code number of                                                                             Dose         ial pressure                                          compound tested                                                                            administered intensity duration                                    ______________________________________                                         70374       2 mg/kg/IV   35 %       20 mm                                      70339       1 mg/kg/IV   80 %      >30 mm                                      70347       2 mg/kg/IV   50 %      >30 mm                                      70405       2 mg/kg/IV   40 %      >60 mm                                      ______________________________________                                    

6. Antiinflammatory properties

These properties bring about a reduction of the local edema, caused by injecting a rat under the plantar with a phlogogenic agent such as carraghenine, following oral administration of compounds of formula (I). As examples the results obtained with a few of the compounds of formula (I) are given in the following Table VII.

                  Table VII                                                        ______________________________________                                                     Dose         Percentage reduc-                                     Code number of                                                                             administered tion of the edema                                     compound tested                                                                            (mg/kg/PO)   (%)                                                   ______________________________________                                         72143        30          70                                                    72196       100          70                                                    ______________________________________                                    

7. Vasodilatory properties

The compounds of formula (I) are able to increase the flow in the coronary vessels of the isolated heat of a guinea pig when they are added to the perfusion liquid of this organ. As an example, by adding 0.5 μg/ml of the compound code number 71562 to the perfusion liquid of the isolated heart of a guinea pig, a 45% increase in the flow of the coronary vessels was observed.

8. Antiarythmic properties

Administered intraperitoneally, the compounds of formula (I) are able to protect the mouse against ventricular fibrillations caused by inhaling chloroform. As examples, the results obtained with different compounds of formula (I) are listed in the following Table VIII.

                  Table VIII                                                       ______________________________________                                                      Antagonism to fibrillations                                                    caused by chloroform with a                                       Code number of                                                                              mouse                                                             compound tested                                                                             DE.sub.50 (mg/kg/IP)                                              ______________________________________                                         72195         60                                                               72188         38                                                               72134         65                                                                7251        100                                                               71562        125                                                               71564        200                                                               72176        100                                                               72142         85                                                                7204        100                                                               ______________________________________                                    

9. Antiulcerous properties

Compounds of formula (I) administered intraduodenally reduce the size of gastric ulcers caused in a rat by ligature of the pylorus (Shay ulcers). As examples, the intradeuodenal administration of 50 mg/kg of the compounds of code numbers 72143 and 7251 bring about a 70% and 65% reduction respectively of the Shay ulcer.

10. Antihistamine properties

The compounds of formula (I) introduced in the survival medium are able to oppose the contracting action of histamine on the isolated ileum of a guinea pig. This activity is calculated by the DE50 of the tested compounds. The results obtained for different compounds of formula (I) are listed in Table IX below.

                  Table IX                                                         ______________________________________                                                        Antihistamine activity                                          Code number of DE50                                                            compound tested                                                                               (μg/ml)                                                      ______________________________________                                         72143          0.25                                                            72196          1                                                               72188          1                                                               72134          1                                                               72176          0.5                                                             72142          0.6                                                             ______________________________________                                    

11. Sedative properties

The compounds of formula (I) administered orally to a mouse reduce the number of explorations in the escape enclosure. As examples, the administration of 100 mg/kg/PO of the compounds of code numbers 71562 and 72142 bring about a 40% reduction in the number of explorations in the escape enclosure in each case.

12. Diuretic properties

The compounds of formula (I) administered orally to a mouse simultaneously with a volume of 1 ml of sodium chloride isotonic solute per 25 g of body weight are able to cause an increase of the volume of urine given compared with controls, this volume being measured for the 4 hours following administration. As examples, the results obtained with different compounds of formula (I) are given in Table X below.

                  Table X                                                          ______________________________________                                                     Dose         Percentage increase                                   Code number of                                                                             administered in urinary elimina-                                   compound tested                                                                            (mg/kg/PO)   tion                                                  ______________________________________                                         72 143      25           70                                                    72 196      12.5         40                                                    72 188      25           40                                                    72 134      50           55                                                     7 251      50           45                                                    71 562      50           70                                                    71 564      12.5         50                                                    72 142      50           55                                                    ______________________________________                                    

13. Antiserotonine properties

The compounds of formula (I) possess a particularly significant antiserotonine property. This property is exhibited in in vivo tests, i.e. antagonism against bronchoconstrictions provoked by intravenous injection of serotonine to guinea pigs (Konzett and Rossler test), and in in vitro tests, i.e. reduction of the contractions of the isolated fundus of rats and the isolated tied uterus, provoked by serotonine.

For purposes of comparison, compounds of the formula (I) were compared, as to their antiserotonine properties, with a respresentative sampling of compounds disclosed in U.S. Pat. No. 3,726,900. The comparison compounds tested have the formula ##STR23##

The specific compounds tested were as follows:

    ______________________________________                                          Code No.  Z                                                                                             ##STR24##                                            ______________________________________                                         69257     CH.sub.2CH.sub.2                                                                              N(CH.sub.3).sub.2                                     70301     CHCH                                                                                           ##STR25##                                            70312     CHCH           N(CH.sub.3).sub.2                                     70315     CHCH                                                                                           ##STR26##                                            ______________________________________                                    

the results of comparative tests carried out under the same conditions were as follows:

                                      Table XI                                     __________________________________________________________________________     Antiserotonine Properties                                                       Code Number of compounds tested                                                           Test of Konzett and Rossler DE.sub.50 (mg/kg/I.V.)                                       LD.sub.50 (mice) (mg/kg/P.O)                                                           ##STR27##                                                                              Antagonisms against contrac- tions                                            of:  Tied uterusFundus of rat                                                  DE.sub.50 (g/ml)DE.sub.50                 __________________________________________________________________________                                          (g/ml)                                    Compounds of the                                                               invention                                                                      70.358    --         1000    --      --      4.94                              70.365    0.6        1250    48      6       3.27                              70.357    0.005      1300    0.38    0.005   0.54                              70.339    0.1        1200    8.3     0.002   0.67                              70.347    0.5        1200    41      0.02    1.78                              72.143    --          300    --      --      4.09                              72.196    --         1100    --      --      3.51                              72.188    0.25       1100    25      --      2.61                              72.142    0.6        1650    36      --      2.12                              72.134    --         1200    --      --      1.72                              72.51     --         >2000   --      --      2.61                              72.04     --         1900    --      --      0.07                              71.562    --         2000    --      --      0.1                               71.564    0.05       3500    14      0.001   0.74                              Compounds of U.S.                                                              Patent No.                                                                     3 726 900                                                                      69.257    0.40        550    72      --      --                                70.301    0.40        425    94      --      --                                70.312    0.43        480    89      --      --                                70.315    1.40        700    200     --      --                                __________________________________________________________________________

14. Anti-depressive properties

The compounds of formula (I) demonstrate no activity when tested by the two principal screening tests for antidepressive activity, namely, opposing the ptosis caused by the intravenous injection of reserpine and potentialization of the lethal effect of yohimbine. In this regard, the compounds of formula I differ unexpectedly from the compounds of U.S. Pat. No. 3,726,900, as shown by comparative testing.

The results of these comparative tests were as follows:

                                      Table XII                                    __________________________________________________________________________     Anti-Depressive Properties                                                     __________________________________________________________________________     Code No. of com-                                                                          LD.sub.50                                                                             Antagonism against ptosis                                                                     Potentialization of lethal                    pounds tested                                                                             mg/kg/P.O.                                                                            caused by reserpine                                                                           effect of yohimbine                           __________________________________________________________________________     70.358     1000   Inactive at 100 mg/kg/PO                                                                      40% at 100 mg/kg/PO                           70.365     1250   Inactive at 100 mg/kg/PO                                                                      Inactive at 100 mg/kg/PO                      70.357     1300   Inactive at 100 mg/kg/PO                                                                      Inactive at 100 mg/kg/PO                      70.339     1200   Inactive at 100 mg/kg/PO                                                                      Inactive at 100 mg/kg/PO                      70.347     1200   Inactive at 100 mg/kg/PO                                                                      Inactive at 100 mg/kg/PO                      70.374     >2000  Inactive at 100 mg/kg/PO                                                                      Inactive at 100 mg/kg/PO                      72.143     300    Inactive at 50 mg/kg/PO                                                                       --                                            72.142     1650   Inactive at 100 mg/kg/PO                                                                      40% at 100 mg/kg/PO                           72.188     1100   Inactive at 50 mg/kg/PO                                                                       --                                            72.134     1200   Inactive at 50 mg/kg/PO                                                                       --                                            7251       >2000  Inactive at 50 mg/kg/PO                                                                       --                                            Compounds of U.S.                                                              Pat. No. 3,726,900                                                             69.257     550    DE.sub.50 : 35 mg/kg/PO                                                                       DE.sub.50 : 10 mg/kg/PO                       70.312     480    DE.sub.50 : 13 mg/kg/PO                                                                       DE.sub.50 : 46 mg/kg/PO                       70.315     700    45% at 75 mg/kg/PO                                                                            --                                            __________________________________________________________________________

The anti-depressive properties of additional analog compounds were tested by the same tests. In these tests, the comparison compounds had the formula ##STR28## The specific compounds tested and the test results are indicated in Table XIII.

                                      Table XIII                                   __________________________________________________________________________     Anti-Depressive Properties                                                     __________________________________________________________________________                      Antagonism against ptosis                                                LD.sub.50                                                                            caused by reserpine                                                                           Potentialization of lethal                                mg/kg/PO                                                                             (DE.sub.50 mg/kg/PO)                                                                          effect of yohimbine                            __________________________________________________________________________     --Z-- = --CH.sub.2 --CH.sub.2 --                                                 R                                                                              CH.sub.3 850     60             50 mg/kg/PO                                    C.sub.4 H.sub.9 (s)                                                                     900     45           ≃ 40% at 50 mg/kg/PO               C.sub.2 H.sub.5                                                                         550   ≃ 50                                                                               --                                          --Z-- = --CH = CH--:                                                             R                                                                              CH.sub.3 750     25             29 mg/kg/PO                                    C.sub.2 H.sub.5                                                                         375     70             60% at 50 mg/kg/PO                             C.sub.3 H.sub.7 (i)                                                                     550   20% at 50 mg/kg/PO                                                                               --                                          __________________________________________________________________________

As is shown by the preceding results and by those given in Table XIV below, the difference between pharmacologically active doses and lethal doses is sufficiently great to allow the use of compounds of formula (I) in therapeutics.

                  Table XIV                                                        ______________________________________                                                       Dose         Percentage of                                       Code numbers of                                                                              administered mortality with                                      compounds tested                                                                             (mg/kg/PO)   mice (%)                                            ______________________________________                                         70 357        1300         ≃ 50                                  70 358        1000         ≃ 50                                  70 365        1250         ≃ 50                                  70 374        2000         0                                                   70 339        1200         ≃ 50                                  70 347        1200         ≃ 50                                  70 405        1600         ≃ 50                                  72 143         300         ≃ 50                                  72 196        1100         ≃ 50                                  72 188        1100         ≃ 50                                  72 134        1200         ≃ 50                                   7 251        2000         0                                                    7 204        1900         ≃ 50                                  71 562        2000         ≃ 50                                  71 564        3500         ≃ 50                                  72 176        3400         ≃ 50                                  72 142        1650         ≃ 50                                  ______________________________________                                    

The compounds of formula I are recommended in the treatment of coughs, vascular and visceral spasms, pains, respiratory depression, hypertension, circulatory insufficiencies, cardiac arythmia, gastroduedenal ulcers, allergies and edemas.

They are administered orally in the form of tablets, pills or gelules containing 25 to 300 mg of active principle (3 to 5 a day) and in the form of a syrup dosed with 0.1 to 2% (3 to 6 soup-spoonfuls a day), parenterally in the form of phials containing 25 to 125 mg of active principle (1 to 3 a day) and rectally in the form of suppositories containing 50 to 200 mg of active principle (1 to 2 a day). 

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
 1. A compound of the formula ##STR29## wherein Z is --CH₂ CH₂ -- or --CH═CH, and the pharmacologically acceptable acid addition salts thereof.
 2. A compound of the formula ##STR30## wherein Z is --CH₂ CH₂ -- or --CH═CH--, and the pharmacologically acceptable acid addition salts thereof.
 3. A compound as claimed in claim 2 in which Z is --CH═CH--.
 4. A compound of the formula ##STR31## wherein Z is --CH₂ CH₂ -- or --CH═CH--, and the pharmacologically acceptable acid addition salts thereof.
 5. A compound as claimed in claim 4 in which Z is --CH═CH--.
 6. A compound of the formula ##STR32## wherein Z is --CH₂ CH₂ -- or --CH═CH--, and the pharmacologically acceptable acid addition salts thereof.
 7. A compound as claimed in claim 6 in which Z is --CH═CH--. 